A single-pool inositol 1,4,5-trisphosphate-receptor-based model for agonist-stimulated oscillations in Ca2+ concentration.

Abstract

Relying on quantitative measurements of Ca2+ activation and inhibition of the inositol 1,4,5-trisphosphate (1P3) receptor in the endoplasmic reticulum, we construct a simplified kinetic model to describe the properties of this channel. Selecting rate constants to fit key kinetic and equilibrium data, we find that the model reproduces a variety of in vivo and in vitro experiments. In combination with Ca2+-ATPase activity for Ca2+ uptake into the endoplasmic reticulum, the model leads to cytoplasmic oscillations in Ca2+ concentration at fixed IP3 concentration and only a single pool of releasable Ca2 , the endoplasmic reticulum. Incorporation of a positive-feedback mechanism of Ca2+ on IP3 production by phospholipase C enriches the properties of the oscillations and leads to oscillations in Ca2+ concentration accompanied by oscillations in I1P3 concentration. We discuss the possible significance of these results for the interpretation of experiments. We construct a simplified model of the IP3 receptor/ channel by assuming that three equivalent and independent subunits are involved in conduction. While it is probable that the subunits are in fact not independent of one another, improvements in this aspect of the model need to await more detailed kinetic measurements. We further assume that each subunit has one IP3 binding site and two Ca2+ binding sites, one for activation, the other for inhibition. Thus, each subunit may exist in eight states with transitions governed by second-order (ai) and first-order (b,) rate constants (Fig. 1) 9895The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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